Carbapenems are a broad class of antibiotic compounds useful for the treatment of infectious diseases including gram positive and negative, aerobic and anaerobic bacteria. U.S. Pat. No. 5,478,820 to Betts, assigned to Zeneca Ltd. teaches carbapenem compounds, salts and hydrolysable esters thereof, of the general formula:
useful as antibiotics, as well as a method for the preparation thereof.
Generally, organic solvents that are used in the crystallization of carbapenem compounds are difficult to remove from the final product because of the limited stability of the compounds. See Takeuchi, Y. et al., Chem. Pharm. Bull. Vol. 41, No. 11, 1993, pg. 1998–2002. These solvents must be reduced to levels that are acceptable for pharmaceutical use. The pharmaceutically acceptable level depends upon the solvent and the maximum daily dose to be administered. Guidelines for what is acceptable are provided by the International Conference on Harmonisation (ICH). For the organic solvents that would be used in pharmaceutical processing and for doses typically used in treatment of bacterial infection, the pharmaceutically acceptable limit would be about 2%. The reduction of organic solvents to pharmaceutically acceptable levels can sometimes be accomplished by heating a compound under vacuum or in a stream of inert gas. However, the process of heating can result in significant degradation of these thermally unstable compounds.
In the present case, the carbapenem solids isolated by crystallization from water/alcohol mixtures become amorphous when the water content of the solid is reduced below a certain level. The organic solvent remaining on the solid when it becomes amorphous is not readily removed and remains above the pharmaceutically acceptable limit. This invention relates to a process for reducing the levels of organic solvents in crystalline carbapenem solids while minimizing degradation of the thermally unstable antibiotic to give a product that is acceptable for pharmaceutical use.